Chronic alcohol abuse significantly increases the incidence of ARDS in critically ill patients at risk for the syndrome (relative risk of 3.7 to1). Approximately 50% of patients with sepsis-associated ARDS have a history of alcohol abuse. However, the absence of biomarkers means that it is difficult to assess at the time of admission a history of alcohol abuse and an increased risk of ARDS. In the alveolar lining fluid, glutathione (GSH) is essential for detoxification and protection against tissue injury during ARDS. In non-cirrhotics, we showed that the alveolar lining fluid GSH was decreased by 80% and shifted to an oxidized state as evidenced by increased GSSG and hydrogen peroxide. Assessment of this chronic oxidant stress in the alveolar space may identify those subjects with an increased risk of ARDS. We recently developed methods to analyze GSH in exhaled breath condensate (EBC), enabling us to monitor alveolar GSH homeostasis and oxidant stress non-invasively. The goal of this proposal is to develop and validate the use of chronic oxidative stress markers in the EBC as an noninvasive tool to predict which critically ill trauma patient has an increased risk for development of ARDS. The aims for this R21 are to determine if markers of oxidant stress (GSH, GSSG, H202, isoprostane or acidification) in the EBC (1) of otherwise healthy alcoholics is a valid non-invasive tool to monitor oxidant stress in the alveolar space, (2) of critically ill trauma patients with a history of alcohol abuse is a valid non-invasive tool to monitor oxidant stress in the alveolar space and (3) can non-invasively predict which critically ill trauma patients have a high risk of developing ARDS. Validation of the EBC technique could potentially be useful in other disease states where decreased alveolar GSH is associated with risk of infection and lung injury such as HIV, cystic fibrosis and interstitial lung disease as well as identify patients that would benefit from antioxidant replacement therapy. Whether it is decreases in GSH or changes in the other oxidant stress markers, we anticipate that from this non-invasive technique we will identify specific cutoff values in the EBC that will serve as a predictive tool to identify those subjects who have chronic oxidative stress in the alveoli (in the absence of lung injury) and have the greatest risk for development of ARDS.